S124: BONE MORPHOGENETIC PROTEIN 2 TRIGGERS OFF AN IMMUNOSUPPRESSIVE EFFECT OF ΓΔ T CELLS IN ACUTE MYELOID LEUKEMIA
Authors: S. Liang, T. Dong, K. Yue, H. Gao, N. Wu, R. Liu, J. Liu, X.-J. Huang
Journal: HemaSphere (2022)

Background: Description of immune landscapes that indulge or restrain survival and proliferation of malignant cells is critical to the improvement of therapeutic strategies. Acute myeloid leukemia (AML) remains a severe life-threatening malignancy and often confronts treatment dilemma in clinic. Although γδ T cells exhibit independent and potent cytotoxicity against leukemic cells in vitro and in the mouse models, efficacy of γδ T cell-based immunotherapy on AML patients has seemed unsatisfying so far. How the anti-AML capacity of γδ T cells is suppressed in vivo is unknown. Aims: In this study, we aim to dissect the abnormal changes and functions of intrinsic γδ T cells in the context of AML and dig out the correlated factors in the AML tumor environment. Methods: 1. Immunophenotyping analyses of γδ T cells in bone marrows from newly diagnosed AML patients (n = 62) were detected using flow cytometry, compared with healthy donors (n=51). The levels of TGF-β family members in the supernatants of bone marrows were detected by ELISA kits. 2. Peripheral blood mononuclear cells (PBMCs) isolated from healthy donors were stimulated with AML blasts and morphogenetic protein 2 (BMP2) to validate clinical phenotypes. Functional experiments were performed to depict the role of a BMP2-induced subset of γδ T cells in the anti-AML activity of effector γδ T cells. 3. To confirm the findings described above, we established human CD34+ cells-implanted mice models followed by injection with luciferase and GFP co-expressing AML cells. Results: The proportions of total γδ T cells and Vδ1+ fraction were not significantly different between AML patients and donors. In contrast, the percentage of Vδ2+ T cells was markedly decreased in AML patients. Meanwhile, a key activating receptor of γδ T cells, NKG2D, was dramatically decreased and regulatory receptors CD25 and PD-1 were increased on Vδ2+ T cells in AML patients. The expansion capacity of Vδ2+ T cells was profoundly impaired in AML patients. The functional impairments of γδ T cells were accompanied with an abnormally increased levels of BMP2, rather than TGF-β, BMP4 and ActivinA, in AML patients. Furthermore, we demonstrated that BMP2 directly induced an aberrant γδ T cells subset expressing Vδ2+CD25+CD127low (abbreviated as BMP2-Vδ2) in PBMCs from healthy donors. Consistently, BMP2-Vδ2 cells were significantly increased in the bone marrows of AML patients compared with donors. The frequencies of BMP2-Vδ2 cells correlated to soluble BMP2 levels and the disease status. Distinct from effector Vδ2 cells, BMP2-Vδ2 not only lost the ability of killing AML cells, but also was able to reduce the anti-AML activity of effector Vδ2 cells after co-cultures. In AML-loaded humanized mice, treatment with BMP2 induced the occurrence of BMP2-Vδ2 cells and reduced the survival rate of mice. Injection of BMP2-Vδ2 cells significantly attenuated the activity of effector Vδ2 cells on the elimination of AML cells in mice. Together, these results demonstrated the immunoregulatory effect of BMP2 on the phenotype and function of γδ T cells in AML microenvironment. Summary/Conclusion: We first reported that dysregulated BMP2 in AML triggered an immunosuppressive subset of γδ T cells, leading to the impairment of anti-AML function of effector γδ T cells. Our findings provide a novel insight into the mechanisms of immunosuppression in the context of leukemia and suggest potential targets for the treatment of AML and other hematopoietic malignancies.